Abstract Pigmented villonodular synovitis (PVNS) is a chronic, progressive neoplastic process that causes the synovial lining of a joint, bursa, or tendon sheath to thicken and overgrow in an aggressive manner with a very low risk of metastasis. This rare condition affects approximately 1.8 people per million?or about 600?per year in the U.S., most commonly appearing in those aged 20 to 45 years old. PVNS can be focal or diffuse. In the diffuse form, the disease process accelerates tendon and joint wear and has a 40-50% rate of local recurrence with traditional treatment strategies, which significantly impacts a patient?s quality of life. The benign but aggressive behavior of PVNS makes treatment challenging as clinicians have to weigh the morbidity of treatment relative to the natural history of the disease process. With the discovery of CSF-1 overexpression in PVNS, new medical therapies targeting the CSF-1 receptor (CSF1R) are within reach, with the potential to reduce surgical morbidity and preserve patient quality of life. Preliminary results are promising; however, no form of chemotherapy has yet been approved for treatment of PVNS and systemic side effects remain a prohibitive problem. Shasqi envisions that methods to locally deliver and activate therapeutics, thus limiting systemic side effects of medications are the solution to conditions such as diffuse PVNS. Therefore, Shasqi is developing a drug delivery technology designed to improve the therapeutic index of drugs that has potential to be applicable to PVNS treatment. The technology consists of a biocompatible biomaterial, and a prodrug (an inactivated drug). Both components contain bioorthogonal reagents that enable them to react only with each other. The biomaterial is physically placed at the desired location in the body. Inactive prodrugs are injected into the blood stream when they are needed. When the prodrugs are proximal to the biomaterial, the bioorthogonal agents quickly react with each other, thus concentrating the prodrug at the biomaterial in the desired location. Finally, the active drug is spontaneously released from the gel to perform its function. This system effectively turns systemic drugs into localized medicines. In PVNS patients, Shasqi proposes application of its technology in adjuvant settings. Following surgical resection, the surgeon would place the biomaterial around the surgical cavity and treat the patient with a prodrug of a CSF1R inhibitor to secure clean margins. Additional gel injections can be given at sites of unresectable tumors. Alternatively, in the case of tumors that or too large to be removed or would require invasive surgical intervention, the technology would be used as a neoadjuvant treatment to improve the outcome of subsequent surgical resection. For this Phase I project, we will synthesize a CSF1R inhibitor prodrug, evaluate the Shasqi platform in a CSF1-dependent cell line, and determine in vivo efficacy in a rat model with established precedent for evaluating CSF1R inhibitors to treat PVNS. In Phase II, we will conduct studies required for IND- enabling safety and efficacy studies in animals. Following Phase II, we will enter human clinical trials.